Abstract 5774: Hypoxia Enhances Platelet-derived Growth Factor Signaling in the Pulmonary Vasculature by HIF-1 α -dependent Downregulation of Protein Tyrosine Phosphatases

Abstract

Background: Platelet-derived growth factor (PDGF) plays a critical role in the development of pulmonary hypertension (PH) as it promotes pulmonary vascular remodeling. PH is frequently associated with severe pulmonary hypoxia. Here we investigated whether hypoxia alters PDGF β receptor ( β PDGFR) signaling. Methods and Results: Chronic hypoxia enhanced PDGF-BB-dependent proliferation and chemotaxis of human pulmonary arterial smooth muscle cells (hPASMC). Pharmacological inhibition of PI3 kinase (PI3K) and PLC γ abrogated these events both under normoxia and hypoxia. While hypoxia did not affect β PDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at the binding sites for PI3K (Y751) and PLC γ (Y1021). The activated β PDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Strikingly, hypoxia decreased the expression of numerous PTPs (TC-PTP, DEP-1, PTP1B, SHP-2), resulting in reduced PTP activity. Putative hypoxia-inducible factor (HIF)-1 α binding sites were identified in the promoter regions of the downregulated PTPs, and hypoxia-induced β PDGFR hyperphosphorylation and PTP downregulation were abolished by HIF-1 α siRNA and by the HIF-1 α inhibitor 2-methoxyestradiol. Immunohistochemistry and quantitative RT-PCR demonstrated that β PDGFR hyperphosphorylation and PTP downregulation were also present in vivo in mice with chronic hypoxia-induced PH. Conclusions: Hypoxia reduces the expression and activity of β PDGFR-antagonizing PTPs in a HIF-1 α -dependent manner, thereby enhancing receptor activation and proliferation/chemotaxis of hPASMC. As hyperphosphorylation of the β PDGFR and downregulation of PTPs also occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other proliferative diseases.